PROJECT SUMMARY/ABSTRACT The long-term objective of our research is to learn and understand etiopathology of type 1 diabetes (T1D) and disease progression, and to develop effective screening, diagnosis, preventive, and treatment strategies in the fight against T1D. In this project, our focus is on genetic associations with disease progression from islet autoimmunity to the onset of T1D, more specifically, discovering novel Conformational Regulatory Segments (CRS) in HLA class I and II genes that are responsible for the progression; CRS can include peptides, nucleotides or other regulatory sequences. Discovering and validating progression-associated CRS within HLA class I and II genes would advance our understanding on the genetic mechanism underlying the disease progression, and further would allow us to develop effective prevention and treatment remedies to slow or even revert the progression. To achieve this short-term goal, we have four specific aims in this proposal: Aim 1 is to select HLA class I/II genes, and to obtain their haplotype-resolved sequences from each gene (with its flanking regions), using the Next Generation Targeted Sequencing technology; Aim 2 is to perform empirical discovery analysis of novel CRS within HLA class I/II genes, using both recursive organizer (ROR) and object-oriented regression analysis (OOR); Aim 3 to perform simulation-based modeling of known or novel CRS alleles within HLA class I/II genes, with respect to their associations with the disease progression. When novel CRS are discovered from the current project, we expand the modeling effort to investigate its structures through molecular modeling approach; and Aim 4 is to carry out functional validation study on progression-associated known in HLA genes and then to expand the functional validation study to validate those novel CRS alleles discovered in this study. While these four aims are highly interactive, four collaborating labs can independently carry out their respective tasks in parallel and can proceed to work on internally generated discoveries during the course of this project.